Malaria is one the world’s most devastating diseases. Several classes of drugs are used to treat malaria. Artemisinin combination therapy is the first line treatment of uncomplicated malaria. The artemisinin derivative, artemisone in conjunction with the Pheroid® drug delivery system, is the focus of this thesis. The impact of the Pheroid® on the bioavailability of artemisone was evaluated in vervet monkeys. The resulting artemisone plasma levels were much lower (Cmax of 47 and 114 ng/mL for reference and Pheroid® test formulations respectively) than expected for the dosages administered (60 mg/kg). The Pheroid® improved the pharmacokinetic profile of artemisone in a clinically significant manner. The metabolism of artemisone was assessed in vitro by using human and monkey liver and intestinal microsomes, and recombinant CYP3A4 enzymes. The Pheroid® inhibits the microsomal metabolism of artemisone. In addition, there is a species difference in artemisone metabolism between man and monkey since the in vitro intrinsic clearance of the reference formulation with monkey liver microsomes is ~8 fold higher in the monkey liver microsomes compared to the human liver microsomes and the estimated in vivo hepatic clearance for the monkey is almost twofold higher than in humans. Artemisone has potent antimalarial activity. Its in vitro efficacy was approximately twofold higher than that of either artesunate or dihydroartemisinin when evaluated against P. falciparum W2, D6, 7G8, TM90-C2B, TM91-C235 and TM93-C1088 parasite strains. The Pheroid® drug delivery system did not improve or inhibit the in vitro efficacy of artemisone or DHA. Artemisone (reference and Pheroid® test formulations) and metabolite M1 abruptly arrested the growth of P. falciparum W2 parasites and induced the formation of dormant ring stages in a manner similar to that of DHA. Interaction of artemisone with the p-glycoprotein (p-gp) efflux transporter was investigated. Artemisone stimulates ATPase activity in a concentration-dependent manner, whereas the Pheroid® inhibited this p-gp ATPase activity. P-gp ATPase activity stimulation was fourfold greater in human than cynomolgus monkey MDR1 expressed insect cell membranes. Artemisone alone and artemisone entrapped in Pheroid® vesicles showed moderate apical to basolateral and high basolateral to apical permeability (Papp) across Caco-2 cells. The Papp efflux ratio of artemisone and artemisone entrapped in Pheroid® vesicles were both >5, and decreased to ~1 when the p-gp inhibitor, verapamil, was added. Therefore, artemisone is a substrate for mammalian p-gp. The cytotoxic properties of Pheroid® on Caco-2 cells were assessed and the pro-Pheroid® seems to be non-toxic at concentrations of 1.25%. Vervet monkey plasma caused antibody-mediated growth inhibition of P. falciparum. Heat inactivated or protein A treatment proved useful in the elimination of the growth-inhibitory activity of the drug-free plasma. Plasma samples containing artemisone could not be analysed by the ex-vivo bioassay method. The dual labelling ROS assay did not prove to be useful in the evaluation of ROS production by artemisone and the Pheroid® delivery system. In conclusion, entrapment of artemisone in the Pheroid® delivery system improves the pharmacokinetic properties of artemisone, but does not improve or inhibit its antimalarial efficacy in vitro. The Pheroid® inhibited both the microsomal metabolism of artemisone and P-gp ATPase activity and was shown to be non-toxic at clinically usable concentrations. / PhD (Pharmaceutics), North-West University, Potchefstroom Campus, 2014

Caffeine is frequently used in cosmetics due to its well-characterised skin permeation properties and is widely incorporated in cosmetic-related products intended for skin (Samah & Heard, 2013:631). Despite its polar characteristics (Dias et al., 1999:41), caffeine is an important biologically and cosmetically active compound (Herman & Herman, 2012:13). This active pharmaceutical ingredient (API) has a broad range of advantages in the world of cosmetics, including the improvement of microcirculation in the capillaries (Lupi et al., 2007:107), showing anti-cellulite activity in the fatty tissue (Velasco et al., 2008:24), anti-oxidation activity in sunscreens & anti-ageing products (Koo et al., 2007:964) and the stimulation of hair growth (Fisher et al., 2007:27). Caffeine has also shown significant decreases in UV-induced skin tumour multiplicity (Lu et al., 2001:5003, 5008) and has been proven to prevent photo-damaged skin, which includes the formation of wrinkles and histological alterations (Mitani et al., 2007:86). It is therefore clear that the challenge for the dermal delivery of the hydrophilic caffeine is for it to be retained in the specific skin layers (dermal delivery) where it can exert its action, rather than to permeate through the skin and into the hydrophilic systemic circulation (transdermal delivery) (Wiechers et al., 2008:10). In this study the calculated skin delivery gap (SDG) values, and the transdermal and dermal delivery of caffeine from three different semi-solid topical formulations were compared. The SDG theory was developed to evaluate the effectiveness of dermal delivery of API from topical formulations and is known as the ratio between the concentration required to achieve minimum effect relative to the concentration obtained at the target site (JW Solutions, 2011). During this study the principle of the SDG was investigated by using the formulating strategy, Formulating for Efficacy (FFE™), which aims to optimise skin delivery of APIs from different formulations. The SDG was therefore implemented and in vitro transdermal studies were utilised to ultimately prove or disprove the hypothesis of SDG on the prediction of the topical delivery of caffeine. The human skin consists of two distinctive layers namely the epidermis (including the stratum corneum (SC) and viable dermis) and the dermis (Menon, 2002:S3). The main barrier to dermal and transdermal permeation is the outermost layer of the skin, the SC (Fang et al., 2007:343). The difference between the target site for dermal and transdermal delivery of APIs is crucial to be mentioned. Dermal delivery includes the delivery of an API to the skin surface, SC, viable epidermis or dermis, whereas transdermal delivery requires the API to permeate all the way through the various skin layers and into the systemic circulation (Wiechers, 2000:42). Since this study involves the optimisation of the topical delivery of caffeine, the physicochemical properties of this API as well as those of the skin should be considered. As mentioned before, caffeine is a rather polar molecule (Dias et al., 1999:41), whereas the SC (lipophilic) provides the rate-limiting barrier to the percutaneous absorption of polar (hydrophilic) molecules, such as caffeine (Barry, 1983:105). Caffeine was incorporated into three different formulations: a gel and two creams (differing only in the ratio of the primary and secondary emollient). The three topical formulations each had different polarities, where the Gel represented the hydrophilic formulation (more polar than the skin), whereas the first cream, Cream 1 (containing 5% DMI and 9% glycerine), served as the intermediate formulation (similar polarity as the SC), and the second cream, Cream 2 (10% DMI and 4% glycerine), was the formulation less polar (therefore more lipophilic) than the SC. Franz cell type transdermal diffusion studies were performed on the three semi-solid formulations (Gel, Cream 1 and Cream 2). The diffusion studies were conducted over a period of 12 h, followed by the tape stripping of the skin directly after each diffusion study. Caucasian female abdominal skin was obtained with consent from willing donors. Ethical approval for the acquisition and use of the donated skin was granted under reference number NWU-00114-11-A5. The formulations each contained 1% of caffeine as API. The skin used for the diffusion studies was prepared with the use of a Zimmer Dermatome®. The receptor phase of each Franz cell was withdrawn at predetermined time intervals and subsequently analysed with high performance liquid chromatography (HPLC) in order to determine the concentration of caffeine that permeated through the skin. Stratum corneum-epidermis (SCE) and epidermis-dermis (ED) samples were prepared and left overnight at a temperature of 4 °C, and they were analysed the following day with the use of HPLC in order to determine the concentration of caffeine that had accumulated in the particular skin layers. The SDG value for each caffeine formulation was calculated and it was compared to the flux and tape stripping results obtained from the diffusion studies. To ultimately prove or disprove the SDG theory, the skin diffusion studies and tape stripping results were used to determine whether any difference occurred in the absorption or penetration of the API from the different formulations into the skin. The formulation with the intermediate polarity (Cream 1) produced the highest transdermal flux of caffeine due to the hydrophilic and lipophilic nature of caffeine and the formulation, respectively. Cream 1 is sufficiently lipophilic to transport caffeine into the SC and at the same time sufficiently hydrophilic (more polar than Cream 2) to cause a greater driving force of caffeine through to the more hydrophilic epidermis, dermis and systemic circulation. The results from the tape stripping yielded that Cream 2 (the more lipophilic formulation) produced the highest concentration of caffeine into the SCE due to the hydrophilic and lipophilic nature of caffeine and the formulation, respectively. The difference in polarity between the formulation and the API in Cream 2 was the greatest compared to the other formulations, which significantly increased the driving force of caffeine to partition into the SC (Wiechers et al., 2004:177). The hydrophilic gel showed the highest concentration of caffeine in the ED layer of the skin due to the hydrophilic compounds formulated in the Gel, which showed greater ability to partition into the aqueous dermis and viable epidermis (Imai et al., 2013:372). Cream 2 had the lowest calculated SDG value compared to that of the Gel and Cream 1. The smaller the delivery gap, the greater the delivery of the API should be into the skin (Wiechers, 2010). Considering this, it was expected that Cream 2 would deliver greater amounts of caffeine into the skin than the more hydrophilic formulations. Cream 2, which showed the lowest calculated SDG value delivered the highest amount of caffeine into the SCE during the diffusion studies. The calculated SDG values therefore are consistent with the concentration of caffeine in the SCE (the lowest SDG value produced the highest concentration of API in the SCE). However, no correlations were found between the calculated SDG values and ED delivery or the flux of caffeine. The final conclusion for this study is that the SDG theory proved to be effective and trustworthy regarding the delivery of caffeine into the SC. / MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2014

Malaria is one the world’s most devastating diseases. Several classes of drugs are used to treat malaria. Artemisinin combination therapy is the first line treatment of uncomplicated malaria. The artemisinin derivative, artemisone in conjunction with the Pheroid® drug delivery system, is the focus of this thesis. The impact of the Pheroid® on the bioavailability of artemisone was evaluated in vervet monkeys. The resulting artemisone plasma levels were much lower (Cmax of 47 and 114 ng/mL for reference and Pheroid® test formulations respectively) than expected for the dosages administered (60 mg/kg). The Pheroid® improved the pharmacokinetic profile of artemisone in a clinically significant manner. The metabolism of artemisone was assessed in vitro by using human and monkey liver and intestinal microsomes, and recombinant CYP3A4 enzymes. The Pheroid® inhibits the microsomal metabolism of artemisone. In addition, there is a species difference in artemisone metabolism between man and monkey since the in vitro intrinsic clearance of the reference formulation with monkey liver microsomes is ~8 fold higher in the monkey liver microsomes compared to the human liver microsomes and the estimated in vivo hepatic clearance for the monkey is almost twofold higher than in humans. Artemisone has potent antimalarial activity. Its in vitro efficacy was approximately twofold higher than that of either artesunate or dihydroartemisinin when evaluated against P. falciparum W2, D6, 7G8, TM90-C2B, TM91-C235 and TM93-C1088 parasite strains. The Pheroid® drug delivery system did not improve or inhibit the in vitro efficacy of artemisone or DHA. Artemisone (reference and Pheroid® test formulations) and metabolite M1 abruptly arrested the growth of P. falciparum W2 parasites and induced the formation of dormant ring stages in a manner similar to that of DHA. Interaction of artemisone with the p-glycoprotein (p-gp) efflux transporter was investigated. Artemisone stimulates ATPase activity in a concentration-dependent manner, whereas the Pheroid® inhibited this p-gp ATPase activity. P-gp ATPase activity stimulation was fourfold greater in human than cynomolgus monkey MDR1 expressed insect cell membranes. Artemisone alone and artemisone entrapped in Pheroid® vesicles showed moderate apical to basolateral and high basolateral to apical permeability (Papp) across Caco-2 cells. The Papp efflux ratio of artemisone and artemisone entrapped in Pheroid® vesicles were both >5, and decreased to ~1 when the p-gp inhibitor, verapamil, was added. Therefore, artemisone is a substrate for mammalian p-gp. The cytotoxic properties of Pheroid® on Caco-2 cells were assessed and the pro-Pheroid® seems to be non-toxic at concentrations of 1.25%. Vervet monkey plasma caused antibody-mediated growth inhibition of P. falciparum. Heat inactivated or protein A treatment proved useful in the elimination of the growth-inhibitory activity of the drug-free plasma. Plasma samples containing artemisone could not be analysed by the ex-vivo bioassay method. The dual labelling ROS assay did not prove to be useful in the evaluation of ROS production by artemisone and the Pheroid® delivery system. In conclusion, entrapment of artemisone in the Pheroid® delivery system improves the pharmacokinetic properties of artemisone, but does not improve or inhibit its antimalarial efficacy in vitro. The Pheroid® inhibited both the microsomal metabolism of artemisone and P-gp ATPase activity and was shown to be non-toxic at clinically usable concentrations. / PhD (Pharmaceutics), North-West University, Potchefstroom Campus, 2014

Caffeine is frequently used in cosmetics due to its well-characterised skin permeation properties and is widely incorporated in cosmetic-related products intended for skin (Samah & Heard, 2013:631). Despite its polar characteristics (Dias et al., 1999:41), caffeine is an important biologically and cosmetically active compound (Herman & Herman, 2012:13). This active pharmaceutical ingredient (API) has a broad range of advantages in the world of cosmetics, including the improvement of microcirculation in the capillaries (Lupi et al., 2007:107), showing anti-cellulite activity in the fatty tissue (Velasco et al., 2008:24), anti-oxidation activity in sunscreens & anti-ageing products (Koo et al., 2007:964) and the stimulation of hair growth (Fisher et al., 2007:27). Caffeine has also shown significant decreases in UV-induced skin tumour multiplicity (Lu et al., 2001:5003, 5008) and has been proven to prevent photo-damaged skin, which includes the formation of wrinkles and histological alterations (Mitani et al., 2007:86). It is therefore clear that the challenge for the dermal delivery of the hydrophilic caffeine is for it to be retained in the specific skin layers (dermal delivery) where it can exert its action, rather than to permeate through the skin and into the hydrophilic systemic circulation (transdermal delivery) (Wiechers et al., 2008:10). In this study the calculated skin delivery gap (SDG) values, and the transdermal and dermal delivery of caffeine from three different semi-solid topical formulations were compared. The SDG theory was developed to evaluate the effectiveness of dermal delivery of API from topical formulations and is known as the ratio between the concentration required to achieve minimum effect relative to the concentration obtained at the target site (JW Solutions, 2011). During this study the principle of the SDG was investigated by using the formulating strategy, Formulating for Efficacy (FFE™), which aims to optimise skin delivery of APIs from different formulations. The SDG was therefore implemented and in vitro transdermal studies were utilised to ultimately prove or disprove the hypothesis of SDG on the prediction of the topical delivery of caffeine. The human skin consists of two distinctive layers namely the epidermis (including the stratum corneum (SC) and viable dermis) and the dermis (Menon, 2002:S3). The main barrier to dermal and transdermal permeation is the outermost layer of the skin, the SC (Fang et al., 2007:343). The difference between the target site for dermal and transdermal delivery of APIs is crucial to be mentioned. Dermal delivery includes the delivery of an API to the skin surface, SC, viable epidermis or dermis, whereas transdermal delivery requires the API to permeate all the way through the various skin layers and into the systemic circulation (Wiechers, 2000:42). Since this study involves the optimisation of the topical delivery of caffeine, the physicochemical properties of this API as well as those of the skin should be considered. As mentioned before, caffeine is a rather polar molecule (Dias et al., 1999:41), whereas the SC (lipophilic) provides the rate-limiting barrier to the percutaneous absorption of polar (hydrophilic) molecules, such as caffeine (Barry, 1983:105). Caffeine was incorporated into three different formulations: a gel and two creams (differing only in the ratio of the primary and secondary emollient). The three topical formulations each had different polarities, where the Gel represented the hydrophilic formulation (more polar than the skin), whereas the first cream, Cream 1 (containing 5% DMI and 9% glycerine), served as the intermediate formulation (similar polarity as the SC), and the second cream, Cream 2 (10% DMI and 4% glycerine), was the formulation less polar (therefore more lipophilic) than the SC. Franz cell type transdermal diffusion studies were performed on the three semi-solid formulations (Gel, Cream 1 and Cream 2). The diffusion studies were conducted over a period of 12 h, followed by the tape stripping of the skin directly after each diffusion study. Caucasian female abdominal skin was obtained with consent from willing donors. Ethical approval for the acquisition and use of the donated skin was granted under reference number NWU-00114-11-A5. The formulations each contained 1% of caffeine as API. The skin used for the diffusion studies was prepared with the use of a Zimmer Dermatome®. The receptor phase of each Franz cell was withdrawn at predetermined time intervals and subsequently analysed with high performance liquid chromatography (HPLC) in order to determine the concentration of caffeine that permeated through the skin. Stratum corneum-epidermis (SCE) and epidermis-dermis (ED) samples were prepared and left overnight at a temperature of 4 °C, and they were analysed the following day with the use of HPLC in order to determine the concentration of caffeine that had accumulated in the particular skin layers. The SDG value for each caffeine formulation was calculated and it was compared to the flux and tape stripping results obtained from the diffusion studies. To ultimately prove or disprove the SDG theory, the skin diffusion studies and tape stripping results were used to determine whether any difference occurred in the absorption or penetration of the API from the different formulations into the skin. The formulation with the intermediate polarity (Cream 1) produced the highest transdermal flux of caffeine due to the hydrophilic and lipophilic nature of caffeine and the formulation, respectively. Cream 1 is sufficiently lipophilic to transport caffeine into the SC and at the same time sufficiently hydrophilic (more polar than Cream 2) to cause a greater driving force of caffeine through to the more hydrophilic epidermis, dermis and systemic circulation. The results from the tape stripping yielded that Cream 2 (the more lipophilic formulation) produced the highest concentration of caffeine into the SCE due to the hydrophilic and lipophilic nature of caffeine and the formulation, respectively. The difference in polarity between the formulation and the API in Cream 2 was the greatest compared to the other formulations, which significantly increased the driving force of caffeine to partition into the SC (Wiechers et al., 2004:177). The hydrophilic gel showed the highest concentration of caffeine in the ED layer of the skin due to the hydrophilic compounds formulated in the Gel, which showed greater ability to partition into the aqueous dermis and viable epidermis (Imai et al., 2013:372). Cream 2 had the lowest calculated SDG value compared to that of the Gel and Cream 1. The smaller the delivery gap, the greater the delivery of the API should be into the skin (Wiechers, 2010). Considering this, it was expected that Cream 2 would deliver greater amounts of caffeine into the skin than the more hydrophilic formulations. Cream 2, which showed the lowest calculated SDG value delivered the highest amount of caffeine into the SCE during the diffusion studies. The calculated SDG values therefore are consistent with the concentration of caffeine in the SCE (the lowest SDG value produced the highest concentration of API in the SCE). However, no correlations were found between the calculated SDG values and ED delivery or the flux of caffeine. The final conclusion for this study is that the SDG theory proved to be effective and trustworthy regarding the delivery of caffeine into the SC. / MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2014

Malaria affects millions of people annually especially in third world countries. Increase in resistance and limited research being conducted adds to the global burden of malaria. Mefloquine, known for unwanted adverse reactions and neurotoxicity, is highly lipophilic and is still used as treatment and prophylaxis. Lipid drug delivery systems are commonly used to increase solubility and efficacy and decrease toxicity. The most generally used lipid drug delivery system is liposomes. The lipid bilayer structure varying in size from 25 nm to 100 μm can entrap both hydrophilic and lipophilic compounds. Similar in structure and size to liposomes, Pheroid™ technology consist of natural fatty acids and is also able to entrap lipophilic and hydrophilic compounds. The aim of this study was to formulate liposomes and Pheroid™ vesicles loaded with mefloquine and evaluate the physiochemical characteristic of the formulations followed by efficacy and toxicity studies. Pheroid™ vesicles and liposomes with and without mefloquine were evaluated in size, morphology, pH and entrapment efficacy during three month accelerated stability testing. Optimization of size determination by flow cytometry lead to accurate determination of size for both Pheroid™ vesicles and liposomes. During the three months stability testing, Pheroid™ vesicles showed a small change in size from 3.07 ± 0.01 μm to approximately 3 μm for all three temperatures. Confocal laser scanning microscopic evaluation of the liposomes showed structures uniform in spherical shape and size. No difference in size or structure between the Pheroid™ vesicles with and without mefloquine were obtained. Significant increase (p=0.027) in size from 6.46 ± 0.01 μm to above 10 μm was observed for liposomes at all the temperatures. Clearly formed lipid bilayer structures were observed on micrographs. With the addition of mefloquine to the liposome formulation, a decrease in the amount of bilayer structures and an increase in oil droplets were found. Entrapment efficacy was determined by firstly separating the entrapped drug from the unentrapped drug utilizing a Sephadex®G50 mini column. This was followed by spectrophotometric evaluation by UV-spectrophotometry at 283 nm. Initial entrapment efficacy of both Pheroid™ vesicles and liposomes was above 60%. An increase in entrapment efficacy was observed for Pheroid™ vesicles. The addition of mefloquine to already formulated Pheroid™ vesicles illustrated entrapment efficacy of 60.14 ± 5.59% after 14 days. Formulations loaded with mefloquine resulted in lower pH values as well as a decrease in pH over time. Optimization of efficacy studies utilizing propidium iodide was necessary due to the similarity in size and shape of the drug delivery systems to erythrocytes. A gating strategy was successfully implemented for the determination of the percentage parasitemia. Efficacy testing of mefloquine loaded in Pheroid™ vesicles and liposomes showed a 186% and 207% decrease in parasitemia levels compared to the control of mefloquine. Toxicity studies conducted include haemolysis and ROS (reactive oxygen species) analysis on erythrocytes as well as cell viability on mouse neuroblastoma cells. Pheroid™ vesicles with and without mefloquine resulted in a dose dependent increase in ROS and haemolysis over time. A dose dependent increase in ROS and haemolysis in both liposome formulations were observed, but to a lesser extent. Mefloquine proved to be neurotoxic with similar results obtained when mefloquine was entrapped in liposomes. Pheroid™ vesicles seem to have neuroprotective properties resulting in higher cell viability. Mefloquine could be entrapped successfully in Pheroid™ vesicles and less in liposomes. Pheroid™ vesicles was more stable over a three months accelerated stability testing with more favourable characteristics. The increase in ROS levels of Pheroid™ vesicles could be responsible for the higher efficacy and haemolytic activity. DL-α-Tocopherol in Pheroid™ vesicles possibly acted as a pro-oxidant due to the presence of iron in the erythrocytes. DL-α-Tocopherol showed possible antioxidant properties in the neurotoxicity evaluation resulting in higher cell viability. Even though liposomes illustrated higher efficacy and little haemolysis and ROS production, no difference in neurotoxicity was observed together with unfavourable properties during stability testing makes this drug delivery system less favourable in comparison to Pheroid™ vesicles. Mefloquine was successfully incorporated into Pheroid™ vesicles resulted in high efficacy and showed possible neuroprotection and therefore makes it an ideal system for treatment of malaria. / Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011

The aim of this study was to explore whether general self–efficacy would moderate the relationship between stress and positive mental health in participants from an African context. Literature supported the concept that stress has a negative influence on mental health and that this interaction may be moderated by cognitive resources. General self–efficacy is a cognitive resource that may act as a moderator in the negative association between stress and positive mental health. Although general self–efficacy is thought to be a universal construct, little empirical research on it has been conducted in an African context. An African socio–cultural context is often described as more collectivistic and characterised by social harmony and interdependence. A sample of 1050 participants from both urban (n=451) and rural (n=599) settings completed Setswana versions of the four relevant questionnaires, i.e. the Mental Health Continuum - Short Form (MHC–SF, Keyes, 2006), used to measure positive mental health, the General Health Questionnaire (GHQ, Goldberg & Hillier, 1979), used to measure the experience of stress, the Generalized Self–Efficacy Scale (GSE, Jerusalem & Schwarzer, 1992) and the New General Self–Efficacy Scale (NGSE, Chen, Gully & Eden, 2001), both measuring general self–efficacy. Data were collected in a quantitative cross–sectional survey design with the aid of 16 trained bilingual (English and Setswana speaking) fieldworkers. Results showed negative correlations between the GHQ (SS, AS, SD, and DS) and MHC–SF (EWB, PWB, and SWB). Results indicated that general self–efficacy moderated the negative effect of manifestation of stress as shown by indices of psychological distress on emotional, psychological and social well–being. Thus, it is found that higher levels of self–efficacy are beneficial for the well–being of individuals in this African sample. / Thesis (M.A. (Clinical Psychology))--North-West University, Potchefstroom Campus, 2011.

The aim of this study was to explore whether general self–efficacy would moderate the relationship between stress and positive mental health in participants from an African context. Literature supported the concept that stress has a negative influence on mental health and that this interaction may be moderated by cognitive resources. General self–efficacy is a cognitive resource that may act as a moderator in the negative association between stress and positive mental health. Although general self–efficacy is thought to be a universal construct, little empirical research on it has been conducted in an African context. An African socio–cultural context is often described as more collectivistic and characterised by social harmony and interdependence. A sample of 1050 participants from both urban (n=451) and rural (n=599) settings completed Setswana versions of the four relevant questionnaires, i.e. the Mental Health Continuum - Short Form (MHC–SF, Keyes, 2006), used to measure positive mental health, the General Health Questionnaire (GHQ, Goldberg & Hillier, 1979), used to measure the experience of stress, the Generalized Self–Efficacy Scale (GSE, Jerusalem & Schwarzer, 1992) and the New General Self–Efficacy Scale (NGSE, Chen, Gully & Eden, 2001), both measuring general self–efficacy. Data were collected in a quantitative cross–sectional survey design with the aid of 16 trained bilingual (English and Setswana speaking) fieldworkers. Results showed negative correlations between the GHQ (SS, AS, SD, and DS) and MHC–SF (EWB, PWB, and SWB). Results indicated that general self–efficacy moderated the negative effect of manifestation of stress as shown by indices of psychological distress on emotional, psychological and social well–being. Thus, it is found that higher levels of self–efficacy are beneficial for the well–being of individuals in this African sample. / Thesis (M.A. (Clinical Psychology))--North-West University, Potchefstroom Campus, 2011.

Malaria affects millions of people annually especially in third world countries. Increase in resistance and limited research being conducted adds to the global burden of malaria. Mefloquine, known for unwanted adverse reactions and neurotoxicity, is highly lipophilic and is still used as treatment and prophylaxis. Lipid drug delivery systems are commonly used to increase solubility and efficacy and decrease toxicity. The most generally used lipid drug delivery system is liposomes. The lipid bilayer structure varying in size from 25 nm to 100 μm can entrap both hydrophilic and lipophilic compounds. Similar in structure and size to liposomes, Pheroid™ technology consist of natural fatty acids and is also able to entrap lipophilic and hydrophilic compounds. The aim of this study was to formulate liposomes and Pheroid™ vesicles loaded with mefloquine and evaluate the physiochemical characteristic of the formulations followed by efficacy and toxicity studies. Pheroid™ vesicles and liposomes with and without mefloquine were evaluated in size, morphology, pH and entrapment efficacy during three month accelerated stability testing. Optimization of size determination by flow cytometry lead to accurate determination of size for both Pheroid™ vesicles and liposomes. During the three months stability testing, Pheroid™ vesicles showed a small change in size from 3.07 ± 0.01 μm to approximately 3 μm for all three temperatures. Confocal laser scanning microscopic evaluation of the liposomes showed structures uniform in spherical shape and size. No difference in size or structure between the Pheroid™ vesicles with and without mefloquine were obtained. Significant increase (p=0.027) in size from 6.46 ± 0.01 μm to above 10 μm was observed for liposomes at all the temperatures. Clearly formed lipid bilayer structures were observed on micrographs. With the addition of mefloquine to the liposome formulation, a decrease in the amount of bilayer structures and an increase in oil droplets were found. Entrapment efficacy was determined by firstly separating the entrapped drug from the unentrapped drug utilizing a Sephadex®G50 mini column. This was followed by spectrophotometric evaluation by UV-spectrophotometry at 283 nm. Initial entrapment efficacy of both Pheroid™ vesicles and liposomes was above 60%. An increase in entrapment efficacy was observed for Pheroid™ vesicles. The addition of mefloquine to already formulated Pheroid™ vesicles illustrated entrapment efficacy of 60.14 ± 5.59% after 14 days. Formulations loaded with mefloquine resulted in lower pH values as well as a decrease in pH over time. Optimization of efficacy studies utilizing propidium iodide was necessary due to the similarity in size and shape of the drug delivery systems to erythrocytes. A gating strategy was successfully implemented for the determination of the percentage parasitemia. Efficacy testing of mefloquine loaded in Pheroid™ vesicles and liposomes showed a 186% and 207% decrease in parasitemia levels compared to the control of mefloquine. Toxicity studies conducted include haemolysis and ROS (reactive oxygen species) analysis on erythrocytes as well as cell viability on mouse neuroblastoma cells. Pheroid™ vesicles with and without mefloquine resulted in a dose dependent increase in ROS and haemolysis over time. A dose dependent increase in ROS and haemolysis in both liposome formulations were observed, but to a lesser extent. Mefloquine proved to be neurotoxic with similar results obtained when mefloquine was entrapped in liposomes. Pheroid™ vesicles seem to have neuroprotective properties resulting in higher cell viability. Mefloquine could be entrapped successfully in Pheroid™ vesicles and less in liposomes. Pheroid™ vesicles was more stable over a three months accelerated stability testing with more favourable characteristics. The increase in ROS levels of Pheroid™ vesicles could be responsible for the higher efficacy and haemolytic activity. DL-α-Tocopherol in Pheroid™ vesicles possibly acted as a pro-oxidant due to the presence of iron in the erythrocytes. DL-α-Tocopherol showed possible antioxidant properties in the neurotoxicity evaluation resulting in higher cell viability. Even though liposomes illustrated higher efficacy and little haemolysis and ROS production, no difference in neurotoxicity was observed together with unfavourable properties during stability testing makes this drug delivery system less favourable in comparison to Pheroid™ vesicles. Mefloquine was successfully incorporated into Pheroid™ vesicles resulted in high efficacy and showed possible neuroprotection and therefore makes it an ideal system for treatment of malaria. / Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011

The main focus of this study is to determine if systems development methodologies are being utilised in the development of electronic learning systems in South Africa and if these methodologies are being applied effectively. Essentially this study can be viewed as exploratory research, utilising a conceptual research model to investigate the relationships between the constructs and measurements. Electronic learning, or e-learning, is being employed to educate millions of learners, students and employees around the world and it is a critical component of modern educational systems. E-learning systems, or learning management systems, as it is known in the field, sit at the heart of these educational systems and are used to systematically deliver on-line content and facilitate the learning experience around that content. There is still much confusion and misconceptions surrounding e-learning and learning management systems abound. This study will try and clarify some of these misconceptions. In e-learning systems, the effective use of information systems is especially relevant as it is used to educate the minds of the future. To ensure that e-learning systems of outstanding quality are being developed, it is therefore crucial that systems development methodologies are being used as they can have a significant impact on the development process. There is a dearth of empirical research available on the use and effectiveness of systems development methodologies in South Africa. This study aims, amongst other things to make a contribution to the availability of empirical results. By empirically evaluating the conceptual research model, utilising a survey as the main research method and statistically analysing the dataset, meaningful results were obtained. This study gave some insights into how learning management system procurement and development is being done in South Africa and revealed that the use of open-source systems currently exceeds the use of proprietary systems. The results of the research showed that systems development methodologies (e.g. Object-Oriented Analysis and Rapid Application Development) are being used effectively in the development of e-learning systems. Strong relationships exist between many of the systems development methodology factors identified (e.g. performance expectancy and the perceived support of the methodology) and the quality and productivity of the development process. This in turn has a strong influence on the impact systems development methodologies have on the quality of learning management systems. / MCom (Computer Science & Information Systems), North-West University, Potchefstroom Campus, 2014

The main focus of this study is to determine if systems development methodologies are being utilised in the development of electronic learning systems in South Africa and if these methodologies are being applied effectively. Essentially this study can be viewed as exploratory research, utilising a conceptual research model to investigate the relationships between the constructs and measurements. Electronic learning, or e-learning, is being employed to educate millions of learners, students and employees around the world and it is a critical component of modern educational systems. E-learning systems, or learning management systems, as it is known in the field, sit at the heart of these educational systems and are used to systematically deliver on-line content and facilitate the learning experience around that content. There is still much confusion and misconceptions surrounding e-learning and learning management systems abound. This study will try and clarify some of these misconceptions. In e-learning systems, the effective use of information systems is especially relevant as it is used to educate the minds of the future. To ensure that e-learning systems of outstanding quality are being developed, it is therefore crucial that systems development methodologies are being used as they can have a significant impact on the development process. There is a dearth of empirical research available on the use and effectiveness of systems development methodologies in South Africa. This study aims, amongst other things to make a contribution to the availability of empirical results. By empirically evaluating the conceptual research model, utilising a survey as the main research method and statistically analysing the dataset, meaningful results were obtained. This study gave some insights into how learning management system procurement and development is being done in South Africa and revealed that the use of open-source systems currently exceeds the use of proprietary systems. The results of the research showed that systems development methodologies (e.g. Object-Oriented Analysis and Rapid Application Development) are being used effectively in the development of e-learning systems. Strong relationships exist between many of the systems development methodology factors identified (e.g. performance expectancy and the perceived support of the methodology) and the quality and productivity of the development process. This in turn has a strong influence on the impact systems development methodologies have on the quality of learning management systems. / MCom (Computer Science & Information Systems), North-West University, Potchefstroom Campus, 2014